CN88101719A - Thienoimidazole also (2, the 1-b) preparation method of thiazole derivative and contain the medicinal product of this derivative - Google Patents

Thienoimidazole also (2, the 1-b) preparation method of thiazole derivative and contain the medicinal product of this derivative Download PDF

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CN88101719A
CN88101719A CN198888101719A CN88101719A CN88101719A CN 88101719 A CN88101719 A CN 88101719A CN 198888101719 A CN198888101719 A CN 198888101719A CN 88101719 A CN88101719 A CN 88101719A CN 88101719 A CN88101719 A CN 88101719A
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迪特尔·伯德
弗朗兹·罗恩斯克
休伯特·彼得·费伯
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
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Abstract

The present invention relates to novel thiophene shown in the formula I and imidazo (2,1-b)-thiazole derivative and pharmaceutical salts thereof, relate to the method for preparing these compounds, and relate to disorders such as cancers that these compounds cause owing to immune defective in treatment or the application aspect the rheumatic arthritis.

Description

The present invention relates to novel thiophene and imidazo (2,1-b) thiazole derivative, its preparation method, and the application of this derivative in medicine that immunity system is played a driving role.
So, the present invention relates to novel generalformula and pharmaceutical salts thereof (if R 3Represent hydrogen)
Figure 88101719_IMG5
Two of A and imidazole ring carbon atoms can form group II a or II b in the formula
Figure 88101719_IMG6
R 1Represent hydrogen, C 1-4Alkyl, fontanel element or trifluoromethyl, R 2Represent hydrogen, fontanel element or trifluoromethyl, and R 3Represent hydrogen or C 1-4Alkyl.
" C described herein 1-4Alkyl " mean the C that straight or branched is saturated 1-4Alkyl, as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl." fontanel element " means chlorine, bromine or fluorine.
As preferred generalformula, wherein R 1Represent hydrogen, R 2Represent chlorine, and R 3Represent hydrogen or methyl.
Particularly preferred compound is:
The 5-(4-chloro-phenyl-) thieno-(2 ', 3 '-4,5) imidazo (2,1-b)-thiazole-6-methyl acetate,
The 7-(4-chloro-phenyl-) thieno-(3 ', 2 '-4,5) imidazo (2,1-b) thiazole-6-methyl acetate,
The 5-(4-chloro-phenyl-) thieno-(2 ', 3 '-4,5) imidazo (2,1-b) thiazole-6-acetate,
The 7-(4-chloro-phenyl-) thieno-(3 ', 2 '-4,5) imidazo (2,1-b) thiazole-6-acetate.
According to the present invention, also (2,1-b) preparation method of thiazole derivative is as follows for Thienoimidazole shown in the formula I
A) in the presence of the water extraction agent, by cyclisation general formula III compound (R wherein 1And R 2As defined above, R 3Be C 1-4Alkyl), (wherein A represents group shown in general formula II a and the II b, R can to obtain formula I 1, R 2And R 3Melt mixture of isomers as defined above), separating isomerism body mixture then,
Figure 88101719_IMG7
B) make acquisition and wherein R thus 3Be C 1-4The generalformula of alkyl can obtain wherein R through alkaline hydrolysis 3Be the generalformula of hydrogen, and
C) necessary, uses inorganic or organic bases with method b) in acquisition and R wherein 3Represent the free acid of the formula I of hydrogen to be converted into pharmaceutical salts.
In the cyclization process of general formula II compound, can use any water extraction agent commonly used.Suitable and Tripyrophosphoric acid or phosphoryl chloride are preferably arranged, they can use as solvent again simultaneously.The cyclisation temperature should be about 60 ℃～110 ℃.Adopt phosphoryl chloride to carry out cyclisation, then temperature reflux temperature preferably.Reaction times is depended on temperature and cyclizing agent, is about 10 minutes to 4 hours.So contain the ester class that A wherein represent the formula I of II a and II b in the fusing isomer mixture that obtains, adopts common method of separating isomers such as recrystallization, column chromatography, distribution chromatography, extracting grade can separate said mixture.By repeatedly obtaining the ester class that A wherein represents II a and do not contain the formula I of isomer from recrystallizing methanol.The suitable practice is to adopt ester mixture to be easy to the nonpolar elution mixture of dissolved, the mixture of being made up of methylene dichloride or chloroform and benzene or toluene for example separates to obtain the ester class that A wherein represents II b and do not contain isomer in the mother liquor that merges with silica gel column chromatography.Then, through wash-out, obtain at first be exactly wherein A represent the ester class of II b.
Under suitable condition, adding solubilizing agent such as methyl alcohol or alcoholic acid simultaneously, by making the ester class and the alkali of formula I, preferably the alkali hydroxide soln azeotropic of equivalent can be with its hydrolysis, and R is the generalformula of hydrogen thereby obtain wherein basically quantitatively.
Adopt inorganic or organic bases the generalformula that obtains and contain free carboxy can be converted into their pharmaceutical salts with ordinary method in step b).For instance, by inciting somebody to action wherein R 3For the above-mentioned generalformula of hydrogen is dissolved in The suitable solvent such as water or lower aliphatic alcohols, add the required alkali of equivalent, just can make this pharmaceutical salts, after this, remove wherein solvent through underpressure distillation through mixing completely.The suitable practice is can carry out recrystallization to salt to handle after separating.
The example of pharmaceutical salts has metal-salt, especially basic metal or alkaline earth salt such as sodium, potassium, magnesium or calcium salt.In addition, the example of other pharmaceutical salts has easy crystalline ammonium salt.The latter can derive from ammoniacal liquor or organic amine and obtain, one, two or three low alkyl groups (cycloalkyl or hydroxyalkyl)-amine for example, low-grade alkylidene diamines or (hydroxyl low-grade alkyl or aryl lower alkyl)-low alkyl group-ammonia alkali, methylamine for example, diethylamine, triethylamine, bicyclohexane amine, trolamine, quadrol, three (methylol) aminomethane, benzyltrimethylammonium hydroxide or the like.
Adopt conventional and be the method that every those skilled in the art were familiar with, with known formula IV (EP-A201,094) and formula V (W.G.Dauben, H.Tilles, J.Org.Chem.15,785-789(1950)) compound is a raw material, can synthesize according to following reaction icon to obtain formula III compound.
Reaction icon
Figure 88101719_IMG8
This novel generalformula and pharmaceutical salts thereof can show splendid immunity system promoter action in test-tube model.
Based on these medicinal properties, this novel cpd can mix use individually or with other active substance, the disease that causes because of the immunity system defectiveness as treatment such as the medicine of cancer disease or rheumatic arthritis, this pharmaceutical dosage form is identical with medicine commonly used.
Generalformula can be used for human body and can use according to conventional administering mode such as oral or parenterai administration mode.With oral way is good, and every day, dosage was about 0.1～100mg/kg body weight, is good with 0.2～20mg/kg body weight.Yet the doctor can be according to analysis and the patient's age to comprehensive situation, specific formula I compound, and kinds of Diseases and formulation strengthen above-mentioned dosage or minimizing.
If material of the present invention is used for prevention, its dosage can change in the scope identical with medicine for treatment.Oral medication is the best approach of prophylactic.
Formula I compound can use individually or with other medical active component, if latter event, then the content of formula I compound is between 0.1～99%, in general, the medical active component is with the form of formation mixtures such as suitable inert additive and/or supporting agent or thinner such as medicinal solvent, gelatin, Sudan Gum-arabic, lactose, starch, Magnesium Stearate, talcum, vegetables oil, polyalkylene glycol, Vaseline and exist.The existence form of pharmaceutical product can be a solid, tablet for example, involucrum tablet, suppository, capsule etc.Or semi-solid, or liquid, for example solution, suspension or emulsion as ointment.Under proper condition, can make it through germicidal treatment, thereby these pharmaceutical products can contain auxiliary agent such as sterilant, stablizer or emulsifying agent are used to improve the salt of its osmotic pressure etc.
Especially, contain in the pharmaceutical product and other The compounds of this invention that useful material of curing the disease is combined.Compound of the present invention with to cure the disease useful material such as above-mentioned auxiliary agent and/or supporting agent or thinner the allotment together, can obtain combination product.
Embodiment 1
The 5-(4-chloro-phenyl-) thieno-(2 ', 3 '-4,5) imidazoles (2,1-b)-thiazole-6-methyl acetate.
With 11.0g(28.9mmol) the 4-(4-chloro-phenyl-)-4-oxygen-3-(1H-thieno-(2,3-d) imidazoles-2-yl) methyl thiobutyrate (formula III, R 1=H, R 2=Cl, R 3=CH 3) be suspended in the 99.0g phosphoryl chloride, with this mixture boiled 10 minutes.Excessive phosphoryl chloride is removed in distillation, and with in the saturated sodium bicarbonate solution and residue.Suspension through the 300ml ethyl acetate extraction once after again each with 100ml ethyl acetate extraction 3 times.Organic phase is merged the back dried over sodium sulfate, through with half gac stirring after filter and evaporation obtains drying.Resistates is with recrystallizing methanol three times, obtains 6.1g yellow crystal [58.2%(theoretical value)], and its fusing point is 159～161 ℃ (methyl alcohol).
1H NMR：（DMSO）
delta（ppm）：7.70（s，4H，Ph-H），7.31，7.25，7.22，7.16，（AB，2H，Th-H），3.92（s，2H，-CH 2-）
13C NMR：（DMSO）
delta（ppm）：169.6（s）152.2（s）150.9（s）135.0（s）130.7（d）129.4（d）127.2（s）126.0（s）122.6（s）121.5（d）117.0（s）115.4（d）52.2（q）32.6（t）
Prepare raw material as follows:
3-bromo-4-(4-chloro-phenyl-)-4-ketobutyric acid methyl esters
With 50.0g(0.221mol) the 4-(4-chloro-phenyl-)-4-ketobutyric acid methyl esters [W.G.Dauben, H.Tillers, J.Org.Chem.15,785～789(1950)] is dissolved in the 250ml Glacial acetic acid, splashes into the glacial acetic acid solution of 3 hydrogen bromides then.Dropwise 35 .3g(0.221mol while stirring) bromine water makes reaction mixture be slightly brown thus.Dropwise, continue to stir this mixture 15 minutes, then, remove most of Glacial acetic acid by distillation.
With in the saturated sodium bicarbonate aqueous solution and resistates, and be that the methylene dichloride of 600ml extracts respectively 3 times with total amount.After organic phase merged, use dried over sodium sulfate, filter again and evaporate (67.2% yellow oil).Develop this product and make its recrystallization in methyl alcohol with methyl alcohol.The result obtains the 65.2g clear crystal, and its fusing point is 48～49 ℃ (methyl alcohol).
The 4-(4-chloro-phenyl-)-4-oxygen-3-(1H-thieno-(2,3-d) imidazoles-2-yl) methyl thiobutyrate
With 3.60g(23.0mmol) 1,3-dihydro-thiophene also (2,3-d) imidazoles-2-thioketones (adopts EP-A201,094 method makes) and 6.40g(20.9mmol) 3-bromo-4-(4-chloro-phenyl-)-4-ketobutyric acid methyl esters is dissolved in the 100ml anhydrous methanol, then this solution refluxed one hour.Steaming desolventizes and develops the oily residue with 5ml ether.Filter resulting crystal with suction filter, then with a small amount of cold ether lixiviate and carry out drying (50 ℃/50mbar).The result obtains the 9.25g yellow crystals; Hydrobromide.
This hydrobromide is suspended in the 20ml ethyl acetate and stirs till gas evaporation stops with saturated sodium bicarbonate solution.Then, remove ethyl acetate under reduced pressure, filter resulting crystal with suction filter, with cold distilled water washing and carry out drying (80 ℃/50mmbar).The result obtains 6.45g pale yellow crystals (81%, theoretical value), and its fusing point is 170～172 ℃ (ethanol).
Embodiment 2
The 5-(4-chloro-phenyl-) thieno-(2 ', 3 '-4,5) imidazo (2,1-b) thiazole-6-methyl acetate
With 6.40g(16.8mmol) the 4-(4-chloro-phenyl-)-4-oxygen-3-(1H-thieno-(2,3-d) imidazoles-2-yl) methyl thiobutyrate is suspended in the 30g Tripyrophosphoric acid, is heated to 80 ℃ while stirring.2.5 after hour, this mixture is inclined to 100ml water, stir then.In this aqueous solution, add the 100ml ethyl acetate,, filter two-phase through HYFLO with suction filter with this mixture heating up to 70 ℃.Then, with filter cake washing for several times with boiling shape ethyl acetate.Each is mutually separated from one another, and the ethyl acetate that with total amount is 300ml is with the water extracted several times.Then, merge organic phase, and, use dried over sodium sulfate, filter and evaporation with the saturated sodium bicarbonate solution extraction.With the mixture recrystallization of two kinds of isomery esters three times, the result obtains 1.20g yellow crystals (19.7%, theoretical value) with methyl alcohol, and its fusing point is 159～161 ℃ (methyl alcohol).NMR: identical with embodiment 1.
Embodiment 3
The 7-(4-chloro-phenyl-) thieno-(3 ', 2 '-4,5) imidazo (2,1-b) thiazole-6-methyl acetate
By the 5-(4-chloro-phenyl-that embodiment 1 is obtained) thieno-(2 ', 3 '-4,5) (2,1-b) the merging mother liquid evaporation in thiazole-6-methyl acetate can obtain 2.7g fusing mixture of isomers to imidazo.Separate this mixture (150g silica gel 60,0.04-0.063mm, eluent: chloroform: benzene=3: 1) by column chromatography.The fore-running that wash-out obtains is divided into title compound, and this cut is handled through the recrystallization of methyl alcohol.The result obtains 1.10g yellow crystals (with the 4-(4-chloro-phenyl-that is obtained by embodiment 1)-4-oxygen-3-(1H-thieno-(2,3-d)-imidazoles-2-yl) methyl thiobutyrate is that benchmark is counted the 10.5%(theoretical value)), its fusing point is 131-133 ℃ (methyl alcohol).
1H NMR：（DMSO）
delta（ppm）：7.69（s，4H，Ph-H），7.20，7.14，6.57，6.51，（AB，2H，Th-H），3.88（s，2H，-CH 2-）
13C NMR：（DMSO）
delta（ppm）：169.7（s）150.8（s）148.2（s）135.0（s）131.1（d）129.3（d）128.8（s）128.3（s）126.1（s）120.2（d）116.5（s）109.9（d）52.2（q）32.6（t）
Embodiment 4
The 7-(4-chloro-phenyl-) thieno-(3 ', 2 '-4,5) imidazo (2,1-b)-thiazole-6-methyl acetate
By making the 5-(4-chloro-phenyl-that obtains by embodiment 2) thieno-(2 ', 3 '-4,5) (2,1-b) the merging mother liquid evaporation in thiazole-6-methyl acetate can obtain 0.60g fusing isomer mixture to imidazo.Adopt column chromatography to separate this mixture (150g silica gel 60,0.04～0.063mm, eluent: chloroform: benzene=3: 1).The fore-running that wash-out obtains is divided into title compound, with methyl alcohol it is carried out recrystallization and handles.The result obtains 0.25g yellow crystals (with the 4-(4-chloro-phenyl-that is obtained by embodiment 2)-4-oxygen-3-(1H-thieno-(2,3-d)-imidazoles-2-yl) methyl thiobutyrate is that benchmark is counted the 4.1%(theoretical value)), its fusing point is 131～133 ℃ (methyl alcohol).NMR: identical with embodiment 3.
Embodiment 5
The 5-(4-chloro-phenyl-) thieno-(2 ', 3 '-4,5) imidazo (2,1-b) thiazole-6-acetate
With 1.70g(4.69mmol) the 5-(4-chloro-phenyl-)-thieno-(2 ', 3 '-4,5) in imidazo (2,1-b) thiazole-6-methyl acetate is suspended in 270mg(4.81mmol) the 8ml water of potassium hydroxide and the solution of 20ml methyl alcohol, and with its backflow 20 minutes.Steaming desolventizes, and residue is dissolved in the 15ml water, with 2N hydrochloric acid resulting suspension is acidified to PH=1, stirs and filters with suction filter after 15 minutes.Residue makes its recrystallization in ethanol with gac behind distilled water wash, dry then (50 ℃/2mbar).The result obtains 1.6g colourless crystallization (98%, theoretical value), and its fusing point is 239～240 ℃ (ethanol).
1H NMR：（DMSO）
delta（ppm）：7.71，（s，4H，Ph-H），7.32，7.26，7.23，7.16，（AB，2H，Th-H），3.82（s，2H，-CH 2-）
13C NMR（DMSO）
delta（ppm）：17.6（s）152.1（s）151.2（s）135.0（s）130.7（d）129.3（d）126.8（s）126.2（s）122.5（s）121.4（d）117.9（s）115.5（d）33.1（t）
Embodiment 6
The 7-(4-chloro-phenyl-) thieno-(3 ', 2 '-4,5) imidazo (2,1-b) thiazole-6-acetate
With 0.30(0.83mmol) the 7-(4-chloro-phenyl-) in thieno-(3 ', 2 '-4,5) imidazo (2,1-b) thiazole-6-methyl acetate is suspended in by 50mg(0.89mmol) potassium hydroxide and 5ml water and the formed solution of 10ml methyl alcohol, and with its backflow.Obtain a limpid solution.Steaming desolventizes, and residue is dissolved in the 15ml water., stirred 15 minutes its acidifying (to PH=1) with 2N hydrochloric acid, filter with suction filter then.Use the distilled water wash residue, make recrystallization in ethanol with gac, carry out then drying (50 ℃/2mbar).The result obtains 0.28g clear crystal (97%, theoretical value), its
Fusing point is 235～238 ℃ (ethanol).
1H NMR：（DMSO）
delta（ppm）：7.70（s，4H，Ph-H），7.20，7.14，6.59，6.53，（AB，2H，Th-H），3.78（s，2H，-CH 2-）
13C NMR：（DMSO）
delta（ppm）：170.7（s）151.1（s）148.2（s）134.9（s）131.1（d）129.3（d）128.8（s）127.9（s）126.4（s）120.1（d）117.4（s）110.0（d）32.9（t）

Claims (9)

1, a kind of formula I compound
Figure 88101719_IMG2
Carbon atom in the formula on A and two imidazole rings forms formula II a or II b group,
Figure 88101719_IMG3
R 1Represent hydrogen, C 1-4Alkyl, fontanel element or CF 3, R 2Represent hydrogen, fontanel element or CF 3, and R 3Represent hydrogen or C 1-4If alkyl is R 3Represent hydrogen, then formula I compound exists with its medicinal form.
2, according to claim 1 described formula I compound and its esters, wherein R 1Represent hydrogen, R 2Represent chlorine and R 3Represent hydrogen or methyl.
3,5-(4-chloro-phenyl-) thieno-(2 ', 3 '-4,5) imidazo (2,1-b) thiazole-6-methyl acetate.
4,7-(4-chloro-phenyl-) thieno-(3 ', 2 '-4,5) imidazo (2,1-b) thiophene-6-methyl acetate.
5,5-(4-chloro-phenyl-) thieno-(2 ', 3 '-4,5) imidazo (2,1-b) thiazole-6-acetate.
6,7-(5-chloro-phenyl-) thieno-(3 ', 2 '-4,5) imidazo (2,1-b) thiazole-6-acetate.
7, the described formula I of preparation claim 1 compound, and the method for its esters is characterized in that
A) in the presence of the water extraction agent,, obtain wherein A and represent formula II a and II b group and R the cyclisation of formula III compound 1, R 2And R 3Melt isomer mixture as defined above, separating isomerism body mixture then,
Figure 88101719_IMG4
R in the formula 1And R 2As defined above, and R 3Represent C 1-4Alkyl,
B) under suitable condition, make acquisition like this and R wherein 3Represent C 1-4The formula I compound of alkyl obtains wherein R through alkaline hydrolysis 3Represent the formula I compound of hydrogen,
C) necessary, with mineral alkali or organic bases with method b) in the formula I free acid that obtains be converted into pharmaceutical salts.
8, a kind of medicinal compositions that contains the described formula I of claim 1 compound or its salt class, the said composition of significant quantity and pharmaceutical excipient, carrier or thinner be compound to can be used to treat the disease that causes owing to immune defective.
9, a kind of medicinal compositions that contains the described formula I of claim 1 compound or its salt class, the said composition of significant quantity and other therapeutical active compound and pharmaceutical excipient, carrier or thinner be compound to can be used to treat the disease that causes owing to immune defective.
CN198888101719A 1987-04-03 1988-04-02 Thienoimidazole also (2, the 1-b) preparation method of thiazole derivative and contain the medicinal product of this derivative Pending CN88101719A (en)

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AT394046B (en) * 1988-09-08 1992-01-27 Chem Pharm Forsch Gmbh NEW THIENO (3 ', 4'-4,5) IMIDAZO (2,1-B) THIAZOLE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE

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US4214089A (en) * 1978-07-18 1980-07-22 American Home Products Corporation Thiazolo[3,2-a]benzimidazoles, imidazo [2,1-b]thiazoles, and related compounds as antineoplastic agents, and enhancers of the immune response
US4293696A (en) * 1980-12-22 1981-10-06 American Home Products Corporation 3-Substituted phenylthiazolo[3'2':1,2]imidazo[4,5-b]pyridine-2-alkanoic acids

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